The goal of the Center for Narcolepsy research is to unravel the cause of narcolepsy, a genetic disorder of REM sleep affecting approximately 250,000 Americans. Since 1973, the Stanford University Canine Narcolepsy Colony has been a indispensable resource in the study of this disorder. The specific aim of this competitive renewal is to maintain and optimate the use of this resource, the only existing animal model of the human disorder. To implement this goal, we will: . maintain a breeding colony of 88 control and genetically narcoleptic dogs . continue to supply animals and tissue to our research teams and to collaborating laboratories . construct a DNA tissue bank from all animals in the colony . continue to develop and expand the Canine Narcolepsy Colony computerized database. This canine colony has been funded by NIH for the past decade. The current level of funding of this grant has become inadequate for maintaining a colony of sufficient size and quality to ensure humane care of the animals and to supply animals for expansion of the colony to 88 animals; improved veterinary care and housing required by law, necessitating increased per diems and involvement of key personnel to optimize the specialized breeding program. The colony is a key resource to study narcolepsy. The main research directions of our approved and funded program project using this resource are: . To investigate the effects of new pharmacological compounds selective for receptor subtypes on canine cataplexy. We expect that the results of these investigations will allow us to elaborate new therapeutic strategies for human narcolepsy. . To determine the regional changes in neurotransmitter and receptor levels underlying canine narcolepsy. . To evaluate the functional significance of these neurochemical abnormalities using local in vivo pharmacology. . To conduct detailed observations of the natural evolution of canine narcolepsy combined with neurochemical/pharmacological testing. . To identify neuronal cells involved in the regulation of canine cataplexy and study their physiological role in relationship with REM sleep and the pathophysiology of the disorder. . To determine the basic genetic defect underlying canine and human narcolepsy. The increased size of the colony and the breeding possibilities will facilitate genetic studies directed toward the isolation of the gene responsible for narcolepsy. In the current funding period we have identified a candidate marker probably linked with narcolepsy and will be pursuing this exciting aspect of the research to the fullest capacity by increasing the breeding program. The existence of this canine colony will also allow us to explore any relationship between narcolepsy and other inherited disorders in Dobermans (e.g., von Willebrand Disease, hypothyroidism, familial glomerulonephropathy). In summary, the canine narcolepsy colony represents a unique opportunity to unravel the pathophysiology of this disorder through a multidisciplinary approach of pharmacology, neurochemistry, physiology, and genetics.